Replication of Associations of Genetic Loci Outside the HLA Region With Susceptibility to Anti–Cyclic Citrullinated Peptide–Negative Rheumatoid Arthritis

Massey, Jonathan; Duffus, Kate; Eyre, Steve; Barton, Anne; Worthington, Jane

doi:10.1002/art.39619

Cited by 34 publications

(26 citation statements)

References 40 publications

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“…Of note, many of the genetic variants identified, such as the ones for HLA-DRB1 and PTPN22, are associated with RA regardless of the serological status, even if the association to ACPA-negative RA was weak [151]. However, certain genetic differences between seropositive and seronegative RA have been revealed, adding to the assumption that RA divides into different subsets with distinct genetic make-up and etiology [151][152][153].…”

Section: Genetic Susceptibilitymentioning

confidence: 99%

Memory T cells specific to citrullinated α-enolase are enriched in the rheumatic joint

Pieper

Dubnovitsky

Gerstner

et al. 2018

Journal of Autoimmunity

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ACPA-positive rheumatoid arthritis (RA) is associated with distinct HLA-DR alleles and immune responses to many citrullinated self-antigens. Herein we investigated the T cell epitope confined within α-enolase in the context of HLA-DRB1*04:01 and assessed the corresponding CD4 T cells in both the circulation and in the rheumatic joint. Comparative crystallographic analyses were performed for the native and citrullinated α-enolase peptides in complex with HLA-DRB1*04:01. HLA-tetramers assembled with either the native or citrullinated peptide were used for ex vivo and in vitro assessment of α-enolase-specific T cells in peripheral blood, synovial fluid and synovial tissue by flow cytometry. The native and modified peptides take a completely conserved structural conformation within the peptide-binding cleft of HLA-DRB1*04:01. The citrulline residue-327 was located N-terminally, protruding towards TCRs. The frequencies of T cells recognizing native eno were similar in synovial fluid and peripheral blood, while in contrast, the frequency of T cells recognizing cit-eno was significantly elevated in synovial fluid compared to peripheral blood (3.6-fold, p = 0.0150). Additionally, citrulline-specific T cells with a memory phenotype were also significantly increased (1.6-fold, p = 0.0052) in synovial fluid compared to peripheral blood. The native T cell epitope confined within α-enolase does not appear to lead to complete negative selection of cognate CD4 T cells. In RA patient samples, only T cells recognizing the citrullinated version of α-enolase were found at elevated frequencies implicating that neo-antigen formation is critical for breach of tolerance.

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Section: Genetic Susceptibilitymentioning

confidence: 99%

Memory T cells specific to citrullinated α-enolase are enriched in the rheumatic joint

Pieper

Dubnovitsky

Gerstner

et al. 2018

Journal of Autoimmunity

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“…The link between PRL and autoimmunity has been proposed to have a genetic background ( 63 , 64 ). The PRL gene is located on the short arm of chromosome 6, near the HLA-DRB1 region, which is known for its association with assorted immune-mediated disorders ( 65 ).…”

Section: Hyperprolactinemia and Autoimmune Diseasesmentioning

confidence: 99%

Prolactin and Autoimmunity

2018

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The great asymmetry of autoimmune diseases between genders represents one of the most enigmatic observations among the mosaic of autoimmunity. Sex hormones are believed to play a crucial role on this dimorphism. The higher prevalence of autoimmunity among women at childbearing ages, disease onset/relapses during pregnancy, and post-partum are some of the arguments that support this hypothesis. Certainly, motherhood represents one of the most remarkable challenges for the immune system, which not only has to allow for the conceptus, but also has to deal with complex endocrine alterations. Hormonal homeostasis is known to exert a crucial influence in achieving a competent and healthy immune system. Prolactin (PRL) has a bioactive function acting as a hormone and a cytokine. It interferes with immune system modulation, mainly inhibiting the negative selection of autoreactive B lymphocytes. Likewise, hyperprolactinemia has been described in relation to the pathogenesis and activity of several autoimmune disorders. Dopamine is an effective inhibitor of PRL secretion due to either a direct influence on the hypophysis or stimulation of postsynaptic dopamine receptors in the hypothalamus, arousing the release of the PRL inhibitory factor. Hence, dopamine agonists have proven to offer clinical benefits among autoimmune patients and represent a promising therapy to be explored. In this review, we attempt to provide a critical overview of the link between PRL, autoimmune diseases, and motherhood.

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“…Patients positive for ACPA and/or RF may be referred to as “seropositive” and make up approximately two thirds of the RA population. Seropositive and seronegative RA seem to have disparate mechanisms in predisposition, since HLA-DRB1 shared epitope (SE) alleles, as well as a number of other genes, associate primarily with ACPA-positive RA [ 2 , 3 ], while other genes have been linked to ACPA-negative disease [ 4 ], suggesting that these subsets are partly separate disease entities.…”

Section: Introductionmentioning

confidence: 99%

Presence of autoantibodies in “seronegative” rheumatoid arthritis associates with classical risk factors and high disease activity

et al. 2020

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Background: Rheumatoid arthritis (RA) is classified as seropositive or seronegative, depending on the presence/ absence of rheumatoid factor (RF), primarily IgM RF, and/or anti-citrullinated protein antibodies (ACPA), commonly detected using anti-cyclic citrullinated peptide (CCP) assays. Known risk factors associate with the more severe seropositive form of RA; less is known about seronegative RA. Here, we examine risk factors and clinical phenotypes in relation to presence of autoantibodies in the RA subset that is traditionally defined as seronegative. Methods: Anti-CCP2 IgG, 19 ACPA fine-specificities, IgM/IgG/IgA RF, anti-carbamylated-protein (CarP) antibodies, and 17 other autoantibodies, were analysed in 2755 RA patients and 370 controls. Antibody prevalence, levels, and co-occurrence were examined, and associations with risk factors and disease activity during 5 years were investigated for different antibody-defined RA subsets. Results: Autoantibodies were detected in a substantial proportion of the traditionally defined seronegative RA subset, with ACPA fine-specificities found in 30%, IgA/IgG RF in 9.4%, and anti-CarP antibodies in 16%, with a 9.6% co-occurrence of at least two types of RA-associated autoantibodies. HLA-DRB1 shared epitope (SE) associated with the presence of ACPA in anti-CCP2-negative RA; in anti-CCP2-positive RA, the SE association was defined by six ACPA fine-specificities with high co-occurrence. Smoking associated with RF, but not with ACPA, in anti-CCP2-negative RA. Presence of ACPA and RF, but not anti-CarP antibodies, in conventionally defined "seronegative" RA, associated with worse clinical outcome. Conclusions: "Seronegative" RA is not truly a seronegative disease subset. Additional screening for ACPA fine-specificities and IgA/IgG RF defines a group of patients that resembles seropositive patients with respect to risk factors and clinical picture and may contribute to earlier diagnosis for a subset of anti-CCP2−/IgM RF− patients with a high need for active treatment.

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Replication of Associations of Genetic Loci Outside the HLA Region With Susceptibility to Anti–Cyclic Citrullinated Peptide–Negative Rheumatoid Arthritis

Cited by 34 publications

References 40 publications

Memory T cells specific to citrullinated α-enolase are enriched in the rheumatic joint

Memory T cells specific to citrullinated α-enolase are enriched in the rheumatic joint

Prolactin and Autoimmunity

Presence of autoantibodies in “seronegative” rheumatoid arthritis associates with classical risk factors and high disease activity

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